The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. However, ARV programs have encountered many challenges, some of which are similar to those observed in North America and some of which differ, including the availability of ARV regimens, widespread use of nevirapine for prevention of mother-to-child HIV transmission, and the presence of non-B HIV subtypes. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring and potential delays in detecting virologic failure on genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease progression. We are currently evaluating the impact of ARVs on HIV incidence among HIV discordant couples. 250 HIV-1 discordant couples were followed between 2004-2009. During this period 32 HIV-1-positive partners were initiated on ARVs since they met immunologic criteria for initiation of therapy. 42 HIV-1 transmissions occurred prior to ARV initiation with an incidence of 9.2/100 pyo. In the 32 couples in which HIV-1 index partners started ARVs, no HIV-1 transmissions occurred while on ARVs. Data from this study as well as others demonstrate that antiretroviral therapy reduces the risk of HIV transmission among HIV-1 discordant couples. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We genotyped 16 HIV-1-infected individuals with virologic failure, who were enrolled in an open-label, randomized clinical trial of short-cycle treatment interruption. All patients receiving efavirenz-containing HAART had >1 efavirenz resistance mutation develop during follow-up. The majority (86%) developed lamivudine resistance during follow-up but no thymidine analog mutations (TAMs) developed during the median duration of virologic failure of one year. In summary, genotype resistance to both efavirenz and lamivudine developed early during the course of treatment after virologic failure. TAMs did not emerge early despite moderate exposure to thymidine analogs thereby preserving the use of these alternative anti-retroviral drugs. We also analyzed antiretroviral drug susceptibility in HIV from participants failing first and second line antiretroviral treatment (ART) regimens in Rakai, Uganda. At baseline, seven of 31 participants had mutations associated with resistance to either nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTIs or NNRTIs). Most participants failing first-line ART had mutations to NNRTIs (86%) and lamivudine (78%), but only 22% had other NRTI mutations. None of the six participants failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings;most programs use clinical or immunological monitoring (IM) only. We compared the genotypic resistance patterns between patients with VLM to those with IM in Kampala, Uganda. Between 2004-2008, 559 antiretroviral nave clients were enrolled in a prospective cohort, initiated ART, and monitored with viral load and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36-40 months and immunologically monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Virologic failure rates at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and 10% in the IM group at 36-40 months. 60% patients in the VLM group compared to 93% in the IM group, (P<0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. 48% of VLM patients had an M184V mutation compared to 87% in the IM group (P<0.0001). Only 8% of VLM patients developed thymidine analogue mutations (TAMS) whereas 51% of IM patients developed TAMS (P<0.0001) with 17% developing 3 or more TAMS. Routine viral load monitoring during the first 3 years of ART reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. We have continued to examine the etiology of severe sepsis in Ugandan hospitals and evaluate interventions to improve mortality outcomes. Dysglycemia during sepsis is associated with poor outcomes in resource rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without benefit of laboratory support. We studied the utility of point-of-care (POC) glucose monitoring to predict mortality in 418 severely septic patients three hospitals in Uganda. Euglycemia occurred in 33.5% of patients, 16.3% of patients were hypoglycemic and 50.2% were hyperglycemic. In multivariate analyses hypoglycemia remained significantly associated with in-hospital mortality. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We have previously published data that individuals who are HSV-2 seropositive at the time of HIV-1 seroconversion had higher HIV viral loads at 5 and 15 months post-seroconversion. Daily suppression of HSV-2 reduces plasma HIV-1 concentrations and has been shown to delay HIV-1 disease progression modestly in one clinical trial. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda. We enrolled 440 HIV-1, HSV-2 dually infected adults with CD4+ T-cell counts 300-400 cells/L and not on antiretroviral therapy in a randomized controlled trial with each arm receiving either acyclovir 400 mg orally twice daily or placebo;participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (p=0.029). In a sub-analysis stratified by baseline VL quintile, the two highest VL quintiles showed the strongest treatment effect (p=0.03) while the lowest two lowest VL quintiles showed no efficacy (p=0.688). Acyclovir reduced the rate of disease progression by 27%, with the greatest impact occurring among individuals with high baseline VL. Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals not yet on antiretroviral treatment, particularly among those with high viral loads. Liver disease is a leading cause of mortality among HIV-infected persons in the US and Europe. However, data regarding the effects of HIV and ART+ on liver disease in Africa are sparse. We conducted a study of 500 HIV-infected participants in an HIV care program in rural Rakai, Uganda who were frequency-matched by age, gender and site to 500 HIV-uninfected participants in a population cohort. The prevalence of hepatitis B coinfection in the study population was 5%. The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (P=0.008). HIV infection was associated with a 50% increase in liver fibrosis. Fibrosis was also associated with male gender, herbal medicine use, heavy alcohol consumption, occupational fishing and chronic HBV infection. Among HIV-infected participants, ART reduced fibrosis risk (P=0.030). The burden of liver fibrosis among HIV-infected rural Ugandans is high. These data suggest that liver disease may represent a significant cause of HIV-related morbidity and mortality in Africa.